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WO2002017879A1 - Coenzyme q sous forme liquide a administration orale et de gout agreable - Google Patents

Coenzyme q sous forme liquide a administration orale et de gout agreable Download PDF

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Publication number
WO2002017879A1
WO2002017879A1 PCT/US2001/025755 US0125755W WO0217879A1 WO 2002017879 A1 WO2002017879 A1 WO 2002017879A1 US 0125755 W US0125755 W US 0125755W WO 0217879 A1 WO0217879 A1 WO 0217879A1
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Prior art keywords
composition
weight
ranging
ubiquinol
amount
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Application number
PCT/US2001/025755
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English (en)
Inventor
Raj K. Chopra
Original Assignee
Chopra Raj K
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Filing date
Publication date
Application filed by Chopra Raj K filed Critical Chopra Raj K
Priority to AU2001283426A priority Critical patent/AU2001283426A1/en
Priority to EP01962230A priority patent/EP1313447A4/fr
Priority to CA002417089A priority patent/CA2417089C/fr
Publication of WO2002017879A1 publication Critical patent/WO2002017879A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin

Definitions

  • the present invention relates to oral compositions comprising coenzyme Q (ubiquinone) or ubiquinol (a reduced form of coenzyme Q) in a liquid form which provides enhanced bioavailability and is palatable to patients, especially children.
  • coenzyme Q ubiquinone
  • ubiquinol a reduced form of coenzyme Q
  • Syrups, elixirs, solutions, and suspensions are traditional dosage forms for oral medication and are particularly useful for certain applications where children represent the main target pool of patients.
  • Liquid formulations at least with respect to a target pool of children, represents a favorable approach for enhancing patient compliance.
  • the sine qua non for enhancing patient compliance via an oral route is a formulation with favorable palatability.
  • Coenzyme Q ubiquinone
  • a dietary supplement is a vitamin-like substance which is used to treat congestive heart failure and other cardiac problems, including heart ailments and diseases such as congestive heart failure, as well as a number of other conditions including high blood pressure, mitochochondrial disorders, including mitochondrial encephalomyopathy, anoxia, lactic acidosis, strokelike symptoms, neurodegenerative diseases, Kearns-Sayre syndrome and Alper's disease, among others.
  • Coenzyme Q is the best known of a group of lipophilic quinones which have the capacity to transfer reducing equivalents or electrons within a lipid phase of cellular membranes. Reduced benzoquinones in general are effective reductants for oxygen or lipid radicals.
  • coenzyme Q can be in reduction of radicals of -tocopherol and ascorbate formed when these antioxidants are oxidized by oxygen or carboxyl radicals.
  • the reduced coenzyme Q would not be a very effective antioxidant because the semiquinone formed by interaction with lipid or oxygen radicals is readily autooxidized with formation of a superoxide radical.
  • Coenzyme Q is essentially insoluble in water and ubiquinol is only slightly better.
  • Coenzyme Q and ubiquinol are poorly absorbed, although their bioavailability may be enhanced in hydrosoluble form. Notwithstanding the increased bioavailability of coenzyne Q and especially, ubiquinol, in hydrosoluble form, the taste of the hydrosoluble form of coenzyme Q and ubiquinol is such that formulation as a pleasant tasting liquid for children as an oral dosage form is simply not possible. This is especially problematic for treating children with coenzyme Q and/or ubiquinol in rare orphan diseases such as mitochondrial cytopathies and other disease states or conditions.
  • the present invention relates to a composition in pharmaceutical dosage form of coenzyme Q or ubiquinol which can be administered to children in an oral dosage form as a pleasant-tasting liquid.
  • the dosage form comprises an effective amount of coenzyme Q or ubiquinol ranging from about 0.05% to about 10%, more preferably about 1% to about 7.5% by weight of the composition in combination with a minor amount of a polysorbate surfactant such as a Tween tm surfactant, most preferably, polysorbate 80, a major amount of a vegetable oil or triglyceride, in further combination with an amount of phospholipid such as hydroxylated lecithin effective to substantially enhance the palatability of ubiquinone or ubiquinol in combination with a sweetener solution as well as an amount of water preferably ranging from about 5% to about 45% by weight.
  • a polysorbate surfactant such as a Tween tm surfactant, most preferably, polysorbate 80
  • phospholipid
  • compositions according to the present invention may optionally comprise solvents, flavorings and optionally, at least one additional surfactant such as a Span surfactant in relatively minor amounts (i.e., in amounts which do not substantially impact the ability of the other components to work together to form a palatable liquid oral dosage form).
  • additional surfactant such as a Span surfactant
  • effective amounts of a lipid soluble reducing agent is preferably included in compositions according to the present invention.
  • coenzyme Q or "ubiquinone”' is used throughout the present specification to describe a group of lipid soluble benzoquinones involved in electron transport in mitochondrial preparations, i.e., in the oxidation of succinate or reduced nicotine adenine dinucleotide (NADH) via the cytochrome system.
  • NADH nicotine adenine dinucleotide
  • the compounds can be described as: coenzyme Q furadenine dinucleotide (NADH) via the cytochrome system.
  • n is 1-12 or ubiquinone (x) in which x designates the total number of carbon atoms in the side chain and can be any multiple of 5. Differences in properties are due to to the difference in the chain length.
  • the preferred ubiquinone for use in the present invention is coenzyme Q ]0 .
  • ubiquinol is used throughout the specification to describe the reduced form of coenzyme Q which is used as an active ubiquinone in compositions according to the present invention.
  • the quinone ring of coenzyme Q is reduced such that the structure of the compound appears as set forth below.
  • n is preferably 10 and is derived from coenzyme Q 10 by the reduction of coenzyme Q w .
  • the amount of ubiquinone/ubiquinol which is included in compositions according to the present invention ranges from about 0.1 % to about 10% (preferably, no more than about 1.5% by weight and even more preferably no more than about 5% by weight of the final liquid composition).
  • the amount of ubiquinol which is included in compositions according to the present invention ranges from about 0.1 to about 10.0 times, more preferably about 1 to about 3 times the amount (in weight percent) of the lipid soluble reducing agent which is included in compositions according to the present invention.
  • surfactant or "emulsifier” is used interchangeably to describe additives to compositions according to the present invention.
  • Surfactants are solubilizers which are used to promote the solubility of the ubiquinone/ubiquinol. These are to be used in combination with a triglyceride or vegetable oil and a phospholipid.
  • Polysorbate surfactants (Tween tm ) are clearly preferred as primary surfactants, but they may be supplemented in the present compositions with minor amounts of secondary surfactants, for example the Span tm surfactants.
  • the amount of surfactant used in the present invention ranges from about 0.1% to about 35%o by weight, more preferably about 1.5% to about 25%, preferably about 2% to about 15%) by weight.
  • Surfactants for use in the present invention are pharmaceutically acceptable and include, for example, the polysorbate surfactants as primary surfactants and complex esters or ester-ethers prepared from hexahydric alcohols, alkylene oxides and fatty acids (the Span tm surfactants) as secondary surfactants.
  • Surfactants which exist in the liquid state at temperatures at or less than formulation temperature generally, about 80 °C or less, more preferably about 50-65 °) are preferred because they can also function as co-solvents or co-solubilizers in the present compositions.
  • the preferred surfactants for use in the present invention include Tween t (polysorbate) surfactants as primary surfactants and Span tm surfactants as optional secondary surfactants, which are well-known in the art for use as stabilizers, surfactants, emulsifiers and thickeners in foods, cosmetics and medical products, among others.
  • Preferred surfactants are those which are in a liquid state during formulation such that the surfactant may also function as a solubilizer (i.e., it has solvent-like properties).
  • a polysorbate (Tween tm ) surfactant is preferred, with a mixture of Span tm and Tween tm surfactants, being optional.
  • the Tween tm or polysorbate type surfactants are oleate esters of sorbitol and its anhydrides copolymerized with a number of moles of ethylene oxide per mole of sorbitol and sorbitol anhydride.
  • the Tween tm surfactants are soluble or well dispersible in water.
  • Preferred Tween tm surfactants include a sorbitan mono-9-octadecenoate poly (oxy- 1,2- etheandiyl) derivative otherwise known as Tween tm 80 or Polysorbate 80.
  • the Span tm surfactants which may be optionally included in the present compositions of the present invention as secondary surfactants (the polysorbate surfactants are the preferred primary surfactants), are partial esters of common fatty acids, such as lauric acid, palmitic acid, stearic acid and oleic acids and hexitol anhydrides such as hexitans and hexides, derived from sorbitol (see below).
  • the sorbitan fatty ester is based upon laurate ester.
  • the ester is based upon stearate ester and in the case of Span 80, the ester is based upon oleic ester.
  • the hydrophilic character of the Span tm surfactants is supplied by free hydroxyl and oxyethylene groups, while the lipophilic character is provided by the long chain fatty groups.
  • the Span 1 " 1 surfactants tend to be oil soluble and dispersible or insoluble in water. However, these surfactants work in tandem with the more water soluble polyhydric alcohol to provide a soluble ubiquinol for soft gel formulations according to the present invention.
  • the use of Span 80 in formulating compositions according to the present invention is preferred.
  • Palatable compositions according to the present invention are those compositions which are agreeable in taste or are otherwise pleasant-tasting in comparison to traditional products..
  • reducing agent is used throughout the specification to describe pharmaceutically acceptable hydrophobic reducing agents which are added to the compositions according to the present invention in effective amounts to convert ubiquinone to ubiquinol during manufacturing and/or to substantially reduce oxidation of ubiquinol to ubiquinone (Coenzyme Q) during manufacturing and/or storage of the compositions according to the present invention.
  • Preferred reducing agents include any reducing agent which is compatible with ubiquinol in pharmaceutical form and is capable of providing the requisite reducing activity to stabilize ubiquinol for storage and is hydrophobic (lipophilic) and otherwise soluble in the triglycerides used in the present invention.
  • the reducing agent is a lipid soluble reducing agent for example, ⁇ -tocopherol (vitamin E), tocopherol esters, ascorbate esters such as ascorbyl palmitate, among others, alpha carotene and ⁇ -carotene, lycopene, flavonoids, riboflavin, curcuminoids, retinol (Vitamin A), retinoic acid, retinoic acid esters, retinol acetate, retinal and related reducing agents, preferably those which may also be used as additives in dietary supplements.
  • vitamin E ⁇ -tocopherol
  • tocopherol esters such ascorbyl palmitate
  • alpha carotene and ⁇ -carotene lycopene
  • flavonoids flavonoids
  • riboflavin curcuminoids
  • retinol (Vitamin A) retinoic acid
  • retinoic acid esters retinol acetate
  • lipid soluble reducing agent including lipid soluble reducings agents which are also biologically active, is preferred because such a composition provides a reducing agent which will most greatly compatibilize with the ubiquinol and the triglycerides (vegetable oil), yet create an emulsion which will mask the rather unpleasant taste of the mixture.
  • Preferred lipid soluble reducing agents are those which are soluble in the triglycerides or vegetable oil and the hydrophobic portion of the phospholipids which are used in the present invention.
  • the inclusion of a solvent as otherwise describhed herein optionally may be added in minor amounts
  • a lipid soluble reducing agent for use in the present invention comprises about 0.05%> to about 15% by weight of the composition, more preferably about 1% to about 7.5% by weight of the final composition.
  • the ratio of reducing agent to ubiquinol in compositions according to the present invention generally ranges from about 1 :10 to about 10:1, more preferably about about 1:5 to about 5:1, more preferably about 1:1 to about 3:1.
  • the amount of reducing agent which is used in the reduction reaction is preferably an excess of that amount required for the reduction reaction on a weight percentage basis. Additional reducing agent may be incorporated into the final formulations after the in situ preparation of ubiquinol from ubiquinone in order to promote the storage stability of the ubiquinol.
  • effective concentrations of reducing agents convert substantially all of the ubiquinone to ubiquinol during manufacturing in an efficient method for preparing ubiquinol.
  • effective concentrations of reducing agents also prevent ubiquinol from being oxidized to ubiquinone, or alternatively reduce any ubiquinone which has been oxidized from ubiquinol during storage of the compositions according to the present invention.
  • phospholipid as used herein shall mean any suitable material of a lipid- like, but amphipathic nature which is a phospholipid, and which preferably has a hydrophobic chain at one end of the molecule and a hydrophilic, charged (anionic) portion at the other end of the molecule. Hydroxylated phospholipids pursuant to the present invention are preferred.
  • the phospholipid is used to help promote the solubility of ubiquinone or ubiquinol within an aqueous solution to be administered orally in combination with a polysorbate surfactant and a triglyceride or oil, to maintain the ubiquinone/ubiquionol in hydrosoluble form in order to promote the bioavailability of the active and promotes the "masking" of the ubiquinone/ubiquinol and other components (especially, the polysorbate surfactant) from the patient's taste receptors in a manner such that the composition has a vastly improved palatability.
  • phospholipids include, for example, phosphatidylcholine (PC), phosphatidylethanolamine (PE), distearoylphosphatidylcholine (DSPC), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidic acid (PA), phosphatidylinositol (PI), sphingomyelin (SPM), and the like, alone or in combination.
  • the phospholipids can be synthetic or derived from natural sources such as egg or soy, but are preferably natural or are obtained from natural products.
  • Some synthetic phospholipids which can be used in the present invention include, for example, dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylglycerol (DMPG).
  • DMPC dimyristoylphosphatidylcholine
  • DMPG dimyristoylphosphatidylglycerol
  • phosphoglycerides which are generally related to triglycerides in that they contain two fatty acid residues and a phosphate ester (generally, a diester) group off of the three hydroxyl groups of glycerine.
  • Phospholipids are preferably included in the present compositions in amounts effective to mask the taste of hydrosoluble ubiquinone/ubiquinol. This amount generally falls within the range from about 0.5%) to about 20%), more preferably about 1% to about 15%>, even more preferably about 1% to about 10% by weight of the final composition.
  • the inclusion of the phospholipid is an important feature in the present invention, inasmuch it is the phospholipid which is believed to surround or encapsulate the ubiquinone and triglyceride in an aqueous medium, thus maintaining the ubiquinone/ubiquinol in hydrosoluble form within phospholipid enapsulated micelles or related structures which maintain the fat soluble components as well as the polysorbate surfactant in hydrosoluble form for enhanced bioavailability of the active, and limiting or even eliminating the chance that foul-tasting components will come into contact with the patient's taste receptors during oral administration. It is an unexpected result that the present compositions would be so effective in providing a hydrosoluble form of ubiquinone/ubiquinol with enhanced bioavailibility from a palatable oral liquid form.
  • hydrosoluble is used throughout the specification to describe a formulation which is in a liquid or liquid-like form and contains sufficient surfactant as well as other components such that when the composition conies into contact with water or an aqueous medium such as gastric juices, the composition will maintain itself in the form of an emulsion or an emulsion-like form, rather than precipitating out of solution. It is the hydrosoluble form of the present invention, which is administered orally, in the form of a liquid, which produces the unexpectedly high bioavailability of ubiquinone/ubiquinol from orally administered compositions according to the present invention.
  • a patient or “subject” is used throughout the specification to describe an animal, generally a human, to whom administration of the compositions according to the present invention is provided.
  • a patient is a child ranging in age from a neonate to a teenager.
  • ⁇ ективное amount is used throughout the specification to describe concentrations or amounts of compounds according to the present invention which are used to produce a favorable result, whether that result relates to a composition's therapeutic or physiological effect or its ability to function for an alternative intended use, for example, a phospholipid which promotes formation and maintainingof ubiquinone/ubiquinol in hydrosoluble form or masks the taste of ubiquinone/ubiquinol or other components within the composition or a reducing agent converting ubiquinone to ubiquinol during manufacturing or to prevent and/or limit the change in or oxidation of the ubiquinol or to function as a solvent in compositions according to the present invention.
  • triglycerides and “vegetable oil” are used synonymously throughout the specification to describe an additive in compositions according to the present invention which may serve as a solubilizer or a compatibilizer of the ubiquinone/ubiquinol with the other components of the present invention. This term is used as it is used by those of ordinary skill in the art, wherein fatty acids are esterifed at the free hydroxyl positions of glycerine, producing triglycerides, which are also the primary component of vegetable oils.
  • Preferred triglycerides for use in the present compositions include vegetable oils including "medium chain triglycerides", which are tri-fatty esters of glycerol wherein the chain length of the fatty acids range from about 10-18 carbon units.
  • Triglycerides are used as solubilizers, diluents and excipients, to compatabilize the formulations and promote uniformity. They are also integral to solubilization of the ubiquinone/ubiquinol and further compatabilization with the phospholipid component of the present invention which results in the masking of the unpleasant taste of ubiquinone/ubiquinol.
  • Vegetable oils for use in the present invention may include, for example, tri- glycerides which may be natural or synthetic (derived from esterification of glycerol and at least one organic acid, saturated or unsaturated, such as for example, such as butyric, caproic, palmitic, stearic, oleic, linoleic or linolenic acids, among numerous others, preferably a fatty organic acid, comprising between 8 and 26 carbon atoms).
  • tri- glycerides which may be natural or synthetic (derived from esterification of glycerol and at least one organic acid, saturated or unsaturated, such as for example, such as butyric, caproic, palmitic, stearic, oleic, linoleic or linolenic acids, among numerous others, preferably a fatty organic acid, comprising between 8 and 26 carbon atoms).
  • Glyceride esters for use in the present invention include vegetable oils derived chiefly from vegetables, seeds or nuts and include, for example, soybean, sunflower, safflower and cottonseed oil; non-drying oils, for example castor and coconut oil; and other oils, such as, for example, palm oil. Hydrogenated vegetable oils also may be used in the present invention.
  • Animal oils are also contemplated for use as glyceride esters and include, for example, fats such as tallow, lard and stearin and liquid fats, such as fish oils, fish-liver oils and other animal oils, including sperm oil, among numerous others.
  • a number of other oils may be used, including C 12 to C 30 (or higher) fatty esters (other than the glyceride esters, which are described above) or any other pharmaceutically acceptable triglyceride.
  • sweetener is used throughout the specification to describe a sweetener, preferably an aqueous solution of a natural or artificial sweetener, which is added to compositions according to the present invention in order to render the composition more palatable.
  • Sweeteners according to the present invention include for example, aspartame, saccharin, cyclamates, sucralose, among numerous other synthetic sweeteners, as well as sugar based sweeteners such as sucrose/water solutions (USP sucrose syrup, about 85%> by weight sucrose and about 15% by weight water), maltose, corn syrup, fructose syrup and related fruit syrup sweeteners, isomalt and sugar alcohols including xylitol, mannitol, maltitol, and sorbitol solutions, among others.
  • the amount of sweetener used in the present compositions ranges from about 0.05%) to about 65% > or more by weight, depending upon the strength of the sweetener used.
  • Preferred sweeteners include the sugar based sweeterners, such as sucrose syrup and corn syrup.
  • solvent is used throughout the specification to describe a liquid into which the ubiquinol and reducing agent is at least partially solubilized, generally in combination with the surfactant and triglyceride as otherwise described herein, is added.
  • Solvents for use in the present invention include any hydrophilic solvent which is pharmaceutically acceptable and which can be used as a solvent, which alone, or in combination with surfacants as otherwise described herein, dissolves ubiquinol and the reducing agent.
  • Preferred solvents for use in the present invention include ethanol and "polyhydric alcohols" a term which is used throughout the present invention to describe any one or more pharmaceutically compatible polyhydric alcohol compounds which are used to solubilize ubiquinol and the reducing agent used in compositions according to the present invention.
  • Polyhydric alcohols which may be used in the present invention include, for example, glycerin (glycerol), propylene glycol and mixtures, thereof.
  • the amount of solvent when used in the present compositions ranges from about 0.1%) to about 25%> by weight, preferably about 1% to about 15% by weight, even more preferably about 1.5% to about 10% by weight.
  • the present invention relates to an orally compatible, pleasant tasting composition in liquid form comprising: i. Ubiquinone or ubiquinol in an effective amount, preferably an effective amount within the range from about 0.05%) to about 10%> by weight of the composition; ii. An effective amount of a primary surfactant falling within the range of about 0.5% to about 35% by weight, preferably about 2% to about 25% by weight of the composition; iii. A triglyceride in an amount ranging from about 0.2% to about 50%> by weight of the composition; iv. A phospholipid in an effective amount ranging from about 0.25% to about 20% by weight, preferably about 1%> to about 10% by weight of the composition; and v. An amount of water ranging from about 1.0% to about 50%) by weight, preferably about 2.5% to about 40-45% by weight of the composition.
  • the compositions also comprise at least one sweetener in an amount ranging from about 0.05%) to about 65% by weight.
  • the present compositions may include one or more of the following: a solvent preferably selected from the group consisting of ethanol or a polyhydric alcohol such as glycerin and propylene glycol in amounts ranging from about 0.1%o to about 25% by weight, more preferably about 0.5 to about 10%) by weight, a secondary surfactant such as a Span tm surfactant preferably in an amount ranging from about 0.01% to about 7.5% by weight of the composition, a lipid soluble reducing agent (in the case where ubiquinol is included in the present compositions) in an amount ranging from about 0.1%o to about 15%, more preferably about 1%> to about 7.5% by weight and flavoring and coloring agents in minor amounts, generally ranging from about 0.005%) to about 5% by weight of the final composition.
  • a solvent preferably selected from the group consisting of ethanol or a polyhydric alcohol such as
  • a pharmaceutically acceptable gelling agent or viscosity control agent such as cellulose gelling agent (hydroxymethylcellulose, hydroxypropylcellulose, among others), guar gum, xanthan gum, etc., among numerous other pharmaceutically acceptable gelling agents may also be added to the compositions in amounts ranging from about 0.005%) to about 3.0%> by weight in an effort to produce a final composition which exhibits increased viscosity.
  • Pharmaceutically acceptable carriers, additives and excipients which are appropriate for oral dosage forms may also be included within the compositions according to the present invention
  • compositions according to the present invention are formulated in oral dosage form as a palatable, pleasant-tasting liquid, including a viscous liquid (i.e., having a viscosity in centipoise units which is consistent with the formation of a flowable gel).
  • a viscous liquid i.e., having a viscosity in centipoise units which is consistent with the formation of a flowable gel.
  • the compositions according to the present invention are generally taken by the subject orally, pursuant to an appropriate pharmaceutical regimen.
  • the compositions according to the present invention because of their enhanced palatability, dramatically improve patient compliance for the administration of ubiquinone/ubiquinol, especially in children.
  • an effective amount of ubiquinone or ubiquinol in powdered or liquid form is added to a mixture of phospholipid and triglycerides in combination with a polysorbate surfactant at elevated temperature.
  • a solvent may be optionally added.
  • sweetener which generally includes water, is added last to the mixture, along with other components such as flavoring agents, coloring agents, preservatives and gelling agent, if applicable.
  • a lipid soluble reducing agent is added to the ubiquinone in the triglycerides, phospholipids and surfactant, optionally in the presence of a solvent, at elevated temperature. This approach results in the reduction of the ubiquinone to ubiquinol.
  • ubiquinol can be produced as a first step and then added to the other components in making oral dosage forms according to the present invention
  • the preferred method is to provide for the in situ preparation of ubiquinol from the less expensive and commercially available ubiquinone (ubiquinol is not commercially available) as described above.
  • the components such as the triglycerides, phospholipids, surfactant and optional solvent and in certain embodiments, lipid soluble reducing agent, are first added together at elevated temperature (generally, at a temperature of about 45-80°C, preferably at a temperature of about 50-60°C) until the components are thoroughly mixed.
  • the components are in a liquid state.
  • coenzyme Q is added to the mixture at elevated temperature as described above and thoroughly mixed into the above components for a sufficient period. If the mixture to which the coenzyme Q is added contains an effective concentration of reducing agent, coenzyme Q will be converted to ubiquinol and the mixture can be used, upon further processing and addition of sweeteners, flavoring agents and the like to provide oral dosage forms which contain ubiquinol.
  • a reducing agent is thereafter added in an amount effective to convert the coenzyme Q to ubiquinol or alternatively, in an amount which not only is effective to convert coenzyme Q to ubiquinol, but also effective to maintain ubiquinol in its reduced state in a storage stable form. Additional reducing agent may be added to compositions according to the present invention at later steps in order to further promote the storage stability of the compositions.
  • the concentration of ubiquinone/ubiquinol to be included in the compositions according to the present invention is an effective amount for treating the patient's disease or condition. This concentration will depend on absorption, distribution, inactivation, and excretion rates of the ubiquinone/ubiquinol and its metabolites as well as other factors known to those of skill in the art. It is to be noted that dosage values will also vary with the severity of the condition to be alleviated. It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed composition.
  • the active ingredient, ubiquinone/ubiquinol may be administered at once, or may be divided into a number of smaller doses to be administered at varying intervals of time.
  • the active components of the present invention can also be mixed with other active materials such as vitamin E (tocopherols), alpha Lipoic acid, L-carnitine (and its derivatives acetyl-L-carnitine and propionyl-L-carnitine) and vitamins and minerals and other components, including omega-3-fatty acids, among others, which do not impair their desired action, or with materials that supplement the desired action provided that the added materials do not change the activity of the included compounds.
  • vitamin E tocopherols
  • alpha Lipoic acid L-carnitine (and its derivatives acetyl-L-carnitine and propionyl-L-carnitine)
  • vitamins and minerals and other components including omega-3-fatty acids, among others, which do not impair their desired action, or with materials that supplement the desired action provided that the added materials do not change the activity of the included compounds.
  • Administration of the active is generally oral, from one to four times daily.
  • the most effective dosage form will depend primarily upon the severity of the condition in the patient to be treated.
  • compositions are used to treat any number of disease states or conditions which respond to the administration of ubiquinone/ubiquinol.
  • the compositions according to the present invention are most preferably used to treat patients for heart disease, including congestive heart failure, high blood pressure, mitochochondrial disorders, including mitochondrial encephalomyopathy and other mitochondrial cytopathies, anoxia, lactic acidosis, neurodegenerative diseases, Kearns-Sayre syndrome and Alper's disease.
  • the patient is a child and the condition or disease state is mitochondrial cytopathy.

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Abstract

Cette invention a trait à une composition sous forme posologique pharmaceutique à base de coenzyme Q ou ubiquinol, pouvant être administrée oralement à des enfants et se présentant sous l'aspect d'un liquide au goût agréable. Cette forme posologique contient une quantité efficace de coenzyme Q ou ubiquinol comprise, en pourcentage pondéral, entre 0,05 et 10 % environ, de préférence entre 1 et 7,5 % de la composition, associée à une quantité minime d'un tensioactif polysorbate tel qu'un tensioactif de type Tweentm, de préférence du polysorbate 80, et à une quantité majeure d'huile végétale ou de triglycérides, en combinaison également avec une certaine quantité de lécithine hydroxylée capable de conserver à l'ubiquinone/ubiquinol sa forme hydrosoluble et destinée à accroître l'appétibilité de l'ubiquinone ou de l'ubiquinol, en association avec une solution sucrante et de l'eau selon des quantités comprises, en pourcentage pondéral, entre 5 et 45 % environ.
PCT/US2001/025755 2000-08-29 2001-08-17 Coenzyme q sous forme liquide a administration orale et de gout agreable WO2002017879A1 (fr)

Priority Applications (3)

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AU2001283426A AU2001283426A1 (en) 2000-08-29 2001-08-17 Palatable oral coenzyme q liquid
EP01962230A EP1313447A4 (fr) 2000-08-29 2001-08-17 Coenzyme q sous forme liquide a administration orale et de gout agreable
CA002417089A CA2417089C (fr) 2000-08-29 2001-08-17 Coenzyme q sous forme liquide a administration orale et de gout agreable

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EP1475363A4 (fr) * 2002-01-18 2006-07-19 Kaneka Corp Procede de stabilisation d'une coenzyme q sb 10 /sb reduite et composition associee
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EP1386905A4 (fr) * 2001-05-09 2005-04-27 Kaneka Corp Solution stable de coenzyme q reduite
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KR100848755B1 (ko) 2002-01-02 2008-07-25 주식회사 두산 포스파티딜세린 함유 액상 조성물 및 그 제조방법
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WO2003061396A1 (fr) 2002-01-18 2003-07-31 Kaneka Corporation Aliments enrichis en ubiquinone
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US7897169B2 (en) 2002-01-18 2011-03-01 Kaneka Corporation Ubiquinol-enriched fat-containing foods
EP1493437A4 (fr) * 2002-03-20 2010-08-11 Kaneka Corp Compositions contre le diabete
EP1870095A4 (fr) * 2005-03-29 2010-10-13 Kaneka Corp Composition permettant d'augmenter l'activite anti-oxydation dans le sang
EP1927349A4 (fr) * 2005-09-22 2010-05-05 Kaneka Corp Composition destinée à prolonger la vie et procédé destiné à prolonger la vie
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EP2090302A4 (fr) * 2006-11-22 2010-01-20 Asahi Kasei Pharma Corp Supplément diététique, agent anti-fatigue, activateur d'endurance physique, aliment fonctionnel, ou produit cosmétique
EP2160180A4 (fr) * 2007-07-04 2013-08-07 Hwail Pharmaceutical Co Ltd Composition de nano-émulsion du coenzyme q10
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US10220007B2 (en) 2008-03-20 2019-03-05 Virun, Inc. Compositions containing non-polar compounds
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ITVA20090052A1 (it) * 2009-07-27 2011-01-28 Ciro Caruso Composizione per il trattamento del cheratocono con tecnica di cross-linking trans-epiteliale o per proteggere strutture interne del globo oculare da raggi uv-a
US11400058B2 (en) 2010-03-12 2022-08-02 Berg Llc Intravenous formulations of coenzyme Q10 (CoQ10) and methods of use thereof
US9320295B2 (en) 2010-03-23 2016-04-26 Virun, Inc. Compositions containing non-polar compounds
ITVA20100044A1 (it) * 2010-05-20 2011-11-21 Ciro Caruso Soluzione oftalmica per proteggere strutture interne del globo oculare da raggi uv-a o per il trattamento del cheratocono con tecnica di cross-linking trans-epiteliale
US10335385B2 (en) 2010-06-21 2019-07-02 Virun, Inc. Composition containing non-polar compounds
US10973763B2 (en) 2011-06-17 2021-04-13 Berg Llc Inhalable pharmaceutical compositions
US9351517B2 (en) 2013-03-15 2016-05-31 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and compositions containing same
US9693574B2 (en) 2013-08-08 2017-07-04 Virun, Inc. Compositions containing water-soluble derivatives of vitamin E mixtures and modified food starch
US10285971B2 (en) 2014-09-18 2019-05-14 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same
US10016363B2 (en) 2014-09-18 2018-07-10 Virun, Inc. Pre-spray emulsions and powders containing non-polar compounds
US9861611B2 (en) 2014-09-18 2018-01-09 Virun, Inc. Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same

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US6441050B1 (en) 2002-08-27
CA2417089C (fr) 2009-08-11
EP1313447A1 (fr) 2003-05-28
AU2001283426A1 (en) 2002-03-13
CA2417089A1 (fr) 2002-03-07
EP1313447A4 (fr) 2009-05-06

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